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1
Fisher, Christal. "Quantitative analysis of the plasma proteome in pre-eclampsia." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/quantitative-analysis-of-the-plasma-proteome-in-preeclampsia(3e207341-ebb9-4cb0-b7ea-34b9b110eda6).html.
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There is currently no clinically useful screening test available to identify nulliparous women at high risk of developing pre-eclampsia. This study aimed to identify novel biomarkers using hypothesis generating proteomic methods applied to plasma samples obtained prior to clinical diagnosis of pre-eclampsia. Plasma samples taken at 15 weeks gestation from women who subsequently developed late pre-eclampsia (> 34 weeks), early pre-eclampsia (< 34 weeks) and two distinct groups of women with uncomplicated pregnancies (each n=12) were pooled. Pooled plasma was immunodepleted, labelled using iTRAQ-8 plex reagent and separated into fractions using high pH reverse phase chromatography. Fractions were analysed by LC-MS/MS and data interrogated using ProteinPilot 3.0. The merits of two immunodepletion systems were compared; the Seppro® IgY 14 -SuperMix LC column system removes up to 100 highly abundant plasma proteins and the Multiple Affinity Removal LC column depletes 14 highly abundant plasma proteins. Removal of more high abundance proteins allowed identification of more, potentially interesting, low abundance proteins, but was less reproducible than removing fewer proteins. Two methods of LC-MS/MS analysis were assessed; the QStar XL qTOF and 5800 MALDI-TOF-TOF. The protein identifications and the quantification data acquired by each method was comparable and complementary and increased the total number of proteins identified. A total of 502 proteins were identified. A stringent two stage analysis was developed to identify candidate proteins which changed in abundance in plasma from women who later developed pre-eclampsia compared to women with uncomplicated pregnancies. Analysis identified a total of 113 proteins which were both reproducibly quantified and changed by more than the expected range of biological variation. Six candidate proteins changed in abundance in the plasma taken from women who subsequently developed early pre-eclampsia were selected for further validation. A high throughput, low cost, method of multiple reaction monitoring which allows relative quantitation without the use of costly isotopically labelled peptides was developed to validate candidate proteins. Candidate proteins were also assessed by western blot and ELISA. Only one candidate protein; platelet basic protein, was validated by all three methods and demonstrated similar increases in the abundance. This investigation suggests that measurement of platelet basic protein at 15 weeks gestation is a novel candidate predictive marker for pre-eclampsia. Validation of platelet basic protein in a large, independent, sample set is required to confirm changes in protein expression and to evaluate potential, alongside other factors, to identify nulliparous women at high risk of developing pre-eclampsia later in pregnancy.
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Mohsenchian, Atefeh. "Biomarker discovery for ALS by using affinity proteomica." Thesis, KTH, Skolan för bioteknologi (BIO), 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-149440.
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Ghobadi, Bita. "Suggestions for optimal biomarker miRNA extraction from plasma of sepsis patients." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-18935.
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Sepsis is a life-threatening organ disfunction, which is caused by a dysfunctional immuneresponse and develops when an infection overwhelms the body’s defense mechanism and causesand uncontrolled inflammatory response. Biomarkers have a great impact on helping diagnosisand treatments of sepsis. The biomarkers, like miRNA, are needed for both more accurate andquicker diagnosis of sepsis in patients. The future diagnostics are looking at other types ofbiomarkers, e.g. miRNA, but low amounts of miRNA are present in biofluids and make itchallenging to quantify. A new methodology is needed which is both accurate and does notrequire a lot of fluid. The aim of this project was to identify which kit of two kits and which oftwo volumes of plasma would lead to the highest concentration of miRNA and highest quality ofmiRNA extracted. This was quantified by using two different volumes, 100 μl and 200 μl, andextracting the two volumes with both exoRNeasy Serum/Plasma midi kit (Qiagen) and TotalRNA Purification kit (Norgen). There was no statistical difference between median miRNAconcentrations between the two volumes within the Qiagen kit. However, the mean miRNAconcentration (0.833 ng/μl) obtained from the Norgen kit (100 μl plasma starting volume) wasstatistically higher than the mean miRNA concentration (0.570 ng/μl) obtained from the samekit with 200 μl, p = 0.033. The optimal kit and volume of this study is the Norgen kit with 100 μl.Further studies are needed to verify these results.
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Papadia, Cinzia. "Plasma citrulline concentration : A biomarker of entercyte absorptive capacity in intestinal failure." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516555.
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Van, der Vaart Maniesh. "Characterization of circulating DNA as a biomarker for genetic aberrations in humans / Maniesh van der Vaart." Thesis, North-West University, 2006. http://hdl.handle.net/10394/1329.
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NI, JIAQIAN. "Plasma Biomarkers for Age-Related Macular Degeneration." Cleveland State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=csu1236700270.
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Caranci, Giovanni. "Plasma alpha synuclein assay in Parkinson's disease and parkinsonisms." Doctoral thesis, Università di Catania, 2013. http://hdl.handle.net/10761/1322.
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In this observational cross-sectional study, using an immunoenzymatic technique we assayed and compared total plasma alpha-synuclein concentrations in 69 patients with Parkinson's disease and 110 age-matched healthy control subjects. Two previously unreported findings concerned gender. First, plasma alpha-synuclein concentrations measured in the more advanced parkinsonian disease
stages decreased in men but not in women. Second, again only in men, plasma alphasynuclein concentration was associated with cognitive impairments, hallucinations, depressed mood and sleep disorders. These findings underline the gender-related differences in parkinsonian patients and indicate plasma alpha-synuclein expression as a potential biological marker for Parkinson's disease progression in men.
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Xu, Haili, Timothy Radabaugh, Zhenqiang Lu, Michael Galligan, Dean Billheimer, Donata Vercelli, Anne L. Wright, Terrence J. Monks, Marilyn Halonen, and Serrine S. Lau. "Exploration of early-life candidate biomarkers for childhood asthma using antibody arrays." WILEY-BLACKWELL, 2016. http://hdl.handle.net/10150/621762.
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Background: Proteomic approaches identifying biomarkers have been applied to asthma to only a very limited extent. Methods: With an antibody array (RayBiotech, Norcross, GA, USA), the relative intensity and rank differences of 444 proteins were compared in 24 plasma samples obtained at age 3, 11 from children with and 12 without asthma diagnoses at ages 5 and 9. Protein candidates identified by antibody array were quantitated by ELISA in an enlarged sample. Proteins found to differentiate children with and without asthma were also examined for association with known Year 1 asthma risk factors, eczema, and wheeze. Results: In the antibody array, four proteins had rank differences between asthma and non-asthma groups (FDR < 0.1). By ELISA, mean log (+/- s.e.m.) erythropoietin (EPO) level (IU/l) was lower (0.750 +/- 0.048 vs. 0.898 +/- 0.035; p = 0.006) and mean (+/- s.e.m.) soluble GP130 (sGP130) level (ng/ml) was higher in the asthma vs. the non-asthma group (302 +/- 13 vs. 270 +/- 8; p = 0.041). The other 2 array proteins (galactin-3 and eotaxin-3) did not differ by ELISA by asthma. EPO related to the asthma risk factor, first year eczema, whereas sGP130 related to first year wheeze. Conclusions: Through two independent assessments, age 3 plasma levels of EPO and sGP130 were found related to childhood asthma.
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Oda, Hiroki. "Plasma microRNAs Are Potential Biomarkers of Acute Rejection After Hindlimb Transplantation in Rats." Kyoto University, 2018. http://hdl.handle.net/2433/232087.
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Tegg, Michelle. "Plasma insulin-degrading enzyme: Characterisation and evaluation as a potential biomarker for Alzheimer's disease." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2014. https://ro.ecu.edu.au/theses/1198.
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Alzheimer’s disease (AD) is increasing in prevalence due to increasing lifespan and altered lifestyle. It is the fourth major cause of death in Western countries, resulting in significant economic and social impact (Von Strauss, et al., 1999; Goate, 1997). There are no blood biomarkers currently accepted for the diagnosis of AD, and the identification of suitable biomarkers would eventually reduce the necessity for invasive, expensive and slow diagnostic procedures, as well as facilitate prognostic studies. An AD blood test would decrease the need for delaying diagnosis due to ambivalent presentation, and allow therapeutic intervention to commence at an earlier and more functional stage for the sufferer, thereby maximising the benefits of treatment. It is also feasible that a blood biomarker would be of use in the development of therapeutic treatments, which are currently inadequate.
Numerous studies have suggested that hyperinsulinemia and type II diabetes (DM2) significantly increase the risk of developing Alzheimer’s disease (AD). Therefore, much research interest has been aimed recently toward determining the putative common mechanisms of these conditions. One enzyme which has been implicated in both AD and DM2 is insulin degrading enzyme (IDE). This project focuses largely on the characterisation of plasma IDE expression and catalytic activity, to help determine potential role/s of IDE in the development of AD, and the suitability of IDE as an AD biomarker. Evidence is also provided to support the concept that IDE impairments may be the common factor that links AD, hyperinsulinemia and DM2.
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Hakimi, Amirmansoor. "Plasma protein profiling for bladder cancer biomarker discovery using UPLC-HDMS^E label-free quantitation." Thesis, University of Leicester, 2013. http://hdl.handle.net/2381/28260.
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In the UK, bladder cancer is the 4th most common cancer in men and 11th most common in women. In 2010, just over 10,000 new cases were diagnosed and 4,900 deaths were recorded. At their first diagnosis, the majority of bladder cancer patients (75-85%) present with non-muscle invasive disease. In 50-70% of these patients the tumour will recur and in 10-20% of them it will progress to muscle invasive disease. Mass spectrometry based proteomics has been chosen for clinical biomarker discovery due to its ability to perform qualitative and quantitative protein profiling on clinical samples. In total 90 plasma samples were used in this study in two groups of disease and control. An optimised and evaluated UPLC-IMS-DIA-MSE label-free quantitation method was used for plasma protein profiling. To our knowledge, this is the first report investigating the biomarkers of bladder cancer incorporating label-free quantitation and UPLC-IMS-DIA-MSE methodology. To assess expression level of proteins of samples in different groups a plan consisting of four data processing packages was used. Each of the packages uses different statistical means by which to identify proteins and/or compare expression levels alteration. Optimisation of the methodology helped in the thorough investigation of the plasma proteome with coverage of up to five orders of magnitude of plasma protein concentration dynamic range. In total, 11 proteins were found as possible markers of diagnosis for bladder cancer. Four of these candidates (afamin, alpha 1-B-glycoprotein, apolipoprotein-A1 and haptoglobin) were previously reported to be urinary markers of bladder cancer. CRP was overexpressed when plasma samples from patients with low grade-Ta tumours were compared to every other sample and may be used as a diagnostic marker. Similarly, afamin and haptoglobin were overexpressed in plasma samples from patients with high grade-high stage tumours when compared to samples from patients with high grade-low stage disease.
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Bourg, Pamela Wilkinson. "Development of a Plasma Biomarker to Test Oxidative Stress in Frail Elders with Traumatic Injury." Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/612129.
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Background: Physically injured elder adults present challenges in the emergent injury phase. Oxidative stress contributes to cellular deterioration, resulting in decreases in physiological reserve. Imbalance of oxidative stress pathways lead to damage and drive the aging process and frailty. Goals of this study were to determine if a new plasma biomarker of oxidative stress is related to: 1) oxidation reduction status in patients who have experienced traumatic injury as well as healthy community dwellers, 2) outcomes of patients who have experienced trauma, 3) frailty measured by established frailty scales in healthy community dwellers. Methods: Prospective study included 1) trauma patients ≥65 admitted to Level I trauma center 2) age, gender matched healthy, community-dwelling participants. Plasma samples tested in duplicate for capacity oxidative reductive potential (cORP, μC; antioxidant reserve), and static oxidative reductive potential (sORP, mV; the current state of oxidative stress). Frailty assessments were performed in healthy participants using established frailty scales. ORP measurements were analyzed using correlation analyses. Univariate analysis analyzed cORP and sORP for differences by the variables gender, age, smoking, diabetes, statin use, vitamin use and any alcohol use in both the injured and healthy populations. Results: 186 subjects included in study (N=93 for both groups). Trauma groups's cORP values were significantly lower in patients with diabetes (p<0.05) and patients that smoked (p<0.01). Similarly the healthy group's cORP was significantly lower for those who smoked and those with diabetes (p<0.05). Non-vitamin use in the healthy group was related to lower cORP values (p<0.05). Trauma patients who smoked and those with diabetes exhibited higher sORP values (p<0.05). In the healthy group, sORP did not differ when considering the variables. No12significant differences were found based on gender, statin or alcohol use for either group. Significant correlation was found for both sORP and cORP with CSHA Clinical Frailty Scale in the healthy group. Conclusion: Findings suggest that the variables of smoking and diabetes are contributory to frailty trajectory. Data suggest the capacity to tolerate oxidative stress, measured by cORP, is lower in aged individuals that smoke or are diabetic and contributes to frailty as a result of oxidative damage.
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Kawata, Keisuke. "SUBCONCUSSIVE HEAD IMPACT EFFECT ON PLASMA EXPRESSION OF S100-BETA AND PINCH PROTEINS IN COLLEGIATE FOOTBALL PLAYERS." Diss., Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/398688.
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KinesiologyPh.D.
In this prospective longitudinal investigation of Division-I collegiate football players, the acute and longer-term effects of repetitive subconcussive impacts on plasma S100β and PINCH levels and concussion-related symptom score were examined. The first aim was to investigate the acute repetitive subconcussive impact effect by comparing the biomarker levels at pre and post full-gear practice, followed by examining the relationship of head impact magnitude and frequency of on acute increases in S100β and PINCH levels and symptom score. Hypotheses for the first aim were that there would be acute increases in plasma S100β and PINCH levels, but no change would be observed in symptom score. A significant relationship between subconcussive impact kinematics and acute changes in outcome measurements would be observed only in S100β. The second aim was to examine the longer-term effect of subconcussive effects on plasma S100β and PINCH levels as well as symptom score compared to the pre-season baseline. It was hypothesized that the players who sustained high frequency and magnitude of subconcussive impact would induce chronically high levels of plasma PINCH compared to the baseline. However, chronic effect would not be found in plasma S100β and symptom score. Independent variables were time (pre vs. post-practice), days (baseline, 1st Pads-OFF, 1st Pads-ON, 2nd Pads-ON, 3rd Pads-ON, 4th Pads-ON, and post-season), and group (higher vs. lower impact group). Dependent variables were the plasma expression of S100β and PINCH and symptom scores at each time point, pre-post differences in the plasma expression of S100β and PINCH and symptom scores, and head impact kinematics (frequency, sum of peak linear and rotational acceleration). This prospective observational study of 22 Division-I collegiate football players included pre-season baseline, pre-season practices [1 helmet-only and 4 full-gear], and post-season follow-up. Acute subconcussive effects were examined using the data from the first full-gear practice. Cumulative subconcussive effects were examined across the study duration (total 12 time points per player). Blood samples and self-reported symptom scores were obtained and blood biomarkers were assessed for pre-post practices and pre-post season. Plasma S100β expression level was assessed using a sandwich-based enzyme-linked immunosorbent assay. Plasma PINCH expression level was assessed using western blot analysis. An accelerometer-embedded mouth guard was employed to measure impact kinematics including number of impacts (hits), peak linear acceleration (PLA), and peak rotational acceleration (PRA). For examining cumulative effects, based on the previously established cut-off value of 173.5 g, players who were exposed average impact magnitudes below 173.5 g per practice were categorized into lower (n = 8) or greater than 173.5 g were categorized into higher (n = 14) impact groups. Data analysis consisted of descriptive and inferential statistics. Student’s t-tests were used to assess group differences in demographic and head impact kinematic data, acute effects using pre-post practice change in concussion-related symptom scores and biomarker levels, and longer-term effects using pre-post season change in concussion-related symptom scores and biomarker levels. Pearson r correlations were used to examine potential relationship between acute increase in outcome measures and head impact kinematics data. Two-way repeated measures ANOVAs were used to identify cumulative subconcussive effects over time in concussion-related symptoms scores and biomarker levels. If necessary, one-way ANOVA as a function of group was used to identify where cumulative effect began compared to the baseline, using Dunnett’s host-hoc correction. The alpha level was set at p < 0.05. A total of 721 head impacts were recorded from the 22 players during the 5 training camp practices. There were significant differences in head impact kinematics per practice between lower and higher impact groups [number of impacts per practice, 1.3 vs. 10.0 (p < .001); linear acceleration, 36.4 vs. 285.6 g (p < .001); rotational acceleration, 2,048.4 vs. 16,497.31 rad/s2 (p < .001), respectively]. There were no changes in self-reported concussion symptoms across the study duration. While there was no change in longer-term effect between pre-season baseline and post-season follow-up in plasma S100β level, robust and acute increase was observed in post-full gear practice (0.111 + 0.01 ng/ml) compared to pre-practice S100β level, (0.048 + 0.01 ng/ml; p < .0001). The acute increase in plasma S100β was significantly and positively correlated to the number of hits (r = 0.636, p = 0.001), sum of peak linear acceleration (r = 0.570, p = .006), and sum of peak rotational acceleration (r = 0.655, p = 0.001) sustained. For plasma PINCH level, there was a 4-fold increase at post-practice compared to that of pre-practice (p = .037), indicating the acute effect of subconcussive impacts. However, the acute increase in plasma PINCH level was independent from frequency and magnitude of impacts sustained, demonstrated by no statistically significant correlations with the number of hits (r = 0.222, p = .333), sum of peak linear acceleration (r = 0.289, p = .204), and sum of peak rotational acceleration (r = 0.297, p = .191). When players were categorized into the lower and higher impact groups and assessed across the 5 training-camp practices, consistently higher levels of plasma S100β and PINCH were found only in the higher impact group at post-practice compared to the baseline. However, plasma level of S100β and PINCH at pre-practice remained stable from the baseline, suggesting the absence of chronic effect from repetitive head impacts. When season-long effects on plasma S100β and PINCH levels were examined, 10 out of 16 players showed increase in plasma PINCH level at post-season compared to the baseline (p = .039) while no significant difference in plasma S100β level. Results from the current study suggest that subconcussive head impacts do not exert self-claimed concussion-related symptoms; however, blood biomarkers detected noticeable acute changes following repetitive subconcussive impacts. Plasma level of S100β protein can be a potential diagnostic measurement to track acute brain burden, and plasma level of PINCH protein may be reflective of the longer-term cumulative brain damage from repetitive head impacts.
Temple University--Theses
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ZILIOTTO, Nicole. "Genomic, vessel wall transcriptomic, and plasma proteomic approaches to investigate multiple sclerosis." Doctoral thesis, Università degli studi di Ferrara, 2019. http://hdl.handle.net/11392/2487975.
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This study was designed to investigate, by several experimental approaches, genes, and proteins associated with multiple sclerosis (MS), an inflammatory and demyelinating disease of the central nervous system (CNS). The study design was aimed to prioritize, by the investigation in patients, potential targets and biomarkers for future mechanistic studies. Through the genomic approach(chpt.10), selected families were investigated by WES for candidate genes from GWAS. The identified low-frequency variants were further investigated in unrelated MS patients. A number of rare and novel mutations were detected, and particularly null variants in the C6orf10 3’ region, in combination with both intra and extra locus low-frequency SNPs. These findings provide the bases for expression studies.
The transcriptomic approach (chpt.6) was focused on the internal jugular vein wall, supported by the interaction between vascular and neurodegenerative mechanisms in MS. This original investigation produced a wealth of information on several biological pathways and permitted the combined transcriptome-protein analysis, which provided intriguing biological and clinical hints.
Analysis at protein level was conducted in plasma by multiplex assays in relation to clinical MS phenotypes and brain MRI measures, as quantitative and “intermediate” phenotypes evaluating disease progression. Higher CCL18 plasma levels were associated with more severe neurodegenerative features, a noticeable finding(chpt.7). The contribution of adhesion molecules, suggested by the transcriptomic analysis, was similarly explored(chpt.8 and 9). Correlation between plasma levels of specific adhesion molecules in MS patients highlights the leukocyte adhesion process in disease.
Increased blood-brain-barrier permeability, a key event in the MS pathophysiology, leads to the irruption of coagulation and hemostasis factors into the CNS, potentially causing an inflammatory response and immune activation. We investigated hemostasis components with main open questions in relation to MS. FXII, the key protease of the coagulation contact activation found deposited in patients’ brain, might participate in adaptive immunity during neuroinflammation. In plasma of MS patients(chpt.4), FXII protein levels were higher than activity, causing a decreased activity/antigen ratio. These findings, corroborated by specifically designed intrinsic thrombin generation assays, might support that FXII contribution in MS is not directly correlated with its “intrinsic” pro-coagulant activity.
Negative regulators of hemostasis (TFPI, ADAMTS13, HCII, TM) with anti-inflammatory properties were also studied, which detected specific patterns of correlations (chpt.5 and 11). Positive association of TFPI with TM, observed in MS patients and not in healthy subjects, would imply that endothelium perturbation acts on multiple release mechanisms. In patients, PAI-1, the key fibrinolysis inhibitor, was positively associated with FXII, and negatively associated with HCII, which suggest disease mechanisms influencing their expression in different tissues with implications in fibrin generation/impaired fibrinolysis, important contributors to neuro-inflammation/degeneration.
Correlations observed between hemostasis components plasma levels and MRI measures, of interest for brain disease mechanisms, did not overcome correction for multiple comparisons.
Extravascular leakage of blood components in MS patients, measured as cerebral microbleeds (CMBs) by MRI, was investigated in relation to plasma levels of hemostasis components. Interestingly, lower ADAMTS13 levels were detected in the MS cohort, in particular in patients with CMBs (chpt.5), who also showed higher VAP-1 levels(chpt.9). These novel findings support the investigation of the plasma protease ADAMTS13, and the amino oxidase/adhesion protein VAP-1, in relation to CMBs. This study provides novel MS disease biomarkers as well as potential drug targetsQuesto studio è stato progettato per indagare attraverso diversi approcci sperimentali i geni e le proteine associate alla sclerosi multipla (SM), una malattia infiammatoria e demielinizzante del sistema nervoso centrale (SNC). L’obiettivo era individuare mediante indagini su pazienti, potenziali bersagli e biomarcatori per futuri studi meccanicistici. Mediante l'approccio genomico(cap.10), le famiglie selezionate sono state studiate attraverso WES per geni candidati da GWAS. Gli SNPs identificati a bassa frequenza sono stati ulteriormente studiati in pazienti indipendenti con SM. L’indagine ha rilevato varianti rare e nuove, tra cui le nulle della regione 3' di C6orf10 in combinazione con SNPs a bassa frequenza a livello intra ed extra locus, fornendo le basi per studi di espressione. L'approccio trascrittomico(cap.6) focalizzato sulla parete interna della vena giugulare, era supportato dall'interazione tra i meccanismi vascolari e quelli neurodegenerativi nella SM. Questa indagine ha prodotto una grande quantità di informazioni su diversi percorsi biologici e ha permesso l'analisi combinata trascrittoma-proteine. L'analisi a livello proteico è stata condotta nel plasma mediante saggi multiplex in relazione ai fenotipi clinici di SM e alle misure cerebrali MRI considerate come fenotipi quantitativi e "intermedi" della progressione della malattia. I livelli plasmatici più alti di CCL18 erano associati a caratteristiche neurodegenerative più gravi(cap.7). Il contributo delle molecole di adesione, suggerito dall'analisi trascrittomica, è stato esplorato in modo analogo(cap.8 e 9). La correlazione tra i livelli plasmatici di specifiche molecole di adesione nei pazienti ha evidenziato il processo di adesione dei leucociti nella malattia. L'aumento della permeabilità della barriera emato-encefalica, evento chiave nella fisiopatologia della SM, porta all’irruzione di fattori emostatici nel SNC, causando una risposta infiammatoria e l’attivazione immunitaria. I componenti dell'emostasi con le principali domande aperte in relazione alla SM sono stati investigati. Il FXII, la proteasi attivatrice della coagulazione da contatto trovata depositata nel cervello dei pazienti, potrebbe partecipare all'immunità adattativa durante la neuroinfiammazione. Nel plasma di pazienti(cap.4) i livelli di proteina del FXII erano superiori all'attività, causando un ridotto rapporto attività/antigene. I risultati corroborati dai saggi di generazione intrinseca di trombina, supporterebbero il contributo del FXII nella SM non attraverso la sua attività pro-coagulante. Lo studio di alcuni inibitori dell'emostasi (TFPI, ADAMTS13, HCII, TM) con proprietà antinfiammatorie, ha rivelato specifici schemi di correlazione(cap.5 e 11). L'associazione positiva di TFPI con TM, osservata nei pazienti e non in soggetti sani, implicherebbe che la perturbazione dell'endotelio agisca su più meccanismi di rilascio. Nei pazienti il PAI-1, l'inibitore chiave della fibrinolisi, era associato positivamente al FXII e negativamente all'HCII, suggerendo meccanismi patologici che influenzano la loro espressione in diversi tessuti con implicazioni nella generazione di fibrina e nella compromissione della fibrinolisi. Le correlazioni osservate tra i livelli plasmatici dei componenti dell'emostasi con le misure di MRI, non hanno superato la correzione per confronti multipli. La perdita extravascolare di sangue misurata come micro sanguinamenti cerebrali (MSC) attraverso MRI è stata studiata nei pazienti in relazione ai livelli plasmatici di componenti dell'emostasi. Livelli più bassi di ADAMTS13 sono stati rilevati nella coorte di SM ed in particolare nei pazienti con MSC(cap.5) che mostravano anche livelli più alti di VAP-1(cap.9). Queste nuove scoperte supportano l'analisi della proteasi ADAMTS13 e l’aminossidasi/proteina di adesione VAP-1 in relazione ai MSC. Questo studio fornisce nuovi biomarcatori della SM e potenziali bersagli farmacologici
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Shenoy, Shamika. "Exosomal microRNA as a sepsis biomarker : Assessing different volumes of plasma for possible quantification of exosomal microRNA." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-17523.
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Sepsis is a medical emergency and it arises from extreme response of the host to an infection. Current diagnosis in sepsis relies on nonspecific clinical signs and culture-based analysis, which is time-consuming. It is critically important for clinicians to follow a protocol to identify sepsis and administer antibiotic therapy without any delay. Sepsis-specific biomarkers are being assessed for early diagnosis and thus improving the outcome of the sepsis patient. Many cellular molecules have been proposed to be sepsis-specific biomarkers. However, these molecules lack specificity and sensitivity. MicroRNA expression in biological fluids, particularly plasma and other tissues is very specific to disease state and are found to be promising diagnostic biomarkers in sepsis. Therefore, it is essential to extract qualitative and sufficient amount of microRNAs from human plasma for the downstream application of two-tailed RT-qPCR method microRNA needed for detection of sepsis patients. The aim of this study was to find optimal volume of plasma required to measure microRNA as sepsis biomarker. The study also included isolating exosomal microRNA from blood samples to check whether blood can be used for extraction. The study was conducted with healthy donor samples and the extraction is performed using Plasma/Serum Exosome Purification (product 58300, Norgen Biotek Corporation, Canada) and RNA Isolation Mini Kit and Total RNA Purification Kit (product 37500, Norgen Biotek Corporation, Canada). The samples were assessed for its quantity and quality by Qubit® and Nanodrop™ technology. Based on the comparison of amount of exosomal microRNA extracted from different plasma volumes, it can be concluded, that increasing volume of plasma may not give higher quantity of microRNA.
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Omar, Jama Sukri. "Tau phosphorylation on threonine 217 as a potential biomarker for neurodegenerative diseases." Thesis, Högskolan i Borås, Akademin för textil, teknik och ekonomi, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:hb:diva-21321.
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Hyperfosforylering av biomarkörproteinet Tau förekommer i flera neurodegenerativa sjukdomar som kallas Taupathies. Proteinets huvudfunktion i människokroppen är att modulera flexibilitet och stabilitet för axonal-mikrotubulin. I Taupathies utlöser hyperfosforyleringen av Tau instabilitet och neurodegenerationen. I dagens läge kan hyperfosforylering av treonin 217 (P217) endast mätas i hjärnan. I den här studien undersöks hyperfosforyleringen av treonin 217 (P217). I syfte att se om nivåerna av P217 är mätbara i cerebrospinalvätska (CSV) och i blodet. Samt för att evaluera hur nivåer av P217 förändras i olika Taupathies, genom att testa hjärnprover från friska kontroller och olika Taupathies. Studien görs för att öka kunskapen om effekten av hyperfosforylering av treonin 217 i Taupathies och för att bidra med en ny provtagningsmetod för P217. Simoa HD-1 Analyzer var instrumentet som användes för analyserna av P217. Det är ett instrument som kan upptäcka onormala nivåer av biomarkörer genom kvantifiering, med hjälp av antikroppar och ett enzym. Enzymet kallas Streptavidin β-galaktosidas och omvandlar en befintlig P217-molekyl i proven till en fluorescerande produkt. Genom Simoa HD-1 Analyzer utvecklades en ultrasensitiv analys med antikropparna P217 och Tau 12, som kunde upptäcka mycket låga nivåer av P217 i hjärnan, CSF och i blod. Förändring av P217-nivåer hittades även i olika Taupathies. De Taupathies med de högsta nivåerna av P217 var Progressiv supranukleär pares, Corticobasal degeneration och Globular glial Taupathies.Hyperphosphorylation of the biomarker protein Tau occurs in many neurodegenerative diseases called Taupathies. The proteins main function in the human body is to modulate flexibility and stability for axonal microtubules. In Taupathies the hyperphosphorylation of the Tau triggers instability and neurodegeneration. Nowdays hyperphoshorylation on threonine 217 (P217) can only be measured in the brain. In this study the hyperphoshorylation on the phosphorylation site of threonine 217 (P217) is examined. In aim to see if levels of P217 is measurable in cerebrospinal fluid (CSF) and in blood. As well to evaluate how P217 variate in different Taupathies, through the use of brain samples from healthy controls and different Taupathies. The study is made for the purpose of enhancing the pure knowledge about the effect of hyperphosphorylation on threonine 217 in Taupathies and to contribute with a new sampling method for P217. Simoa HD-1 Analyzer was the key instrument of the analyses of P217. It’s an instrument which can detect abnormal levels of biomarkers through quantification, with help of antibodies and an enzyme. The enzyme is called Streptavidin β-galactosidase and converts an existing P217 molecule in the samples to a fluoresce product. Through the use of Simoa HD-1 Analyzer an ultrasensitive assay with antibodies P217 and Tau 12 was developed which could detect very low levels of P217 in brain, CSF and in blood. Variation of P217 levels was also found in different Taupathies. The Taupathies with the highest levels of P217 was Progressive supranuclear palsy, Corticobasal Degeneration and Globular glial Taupathies.
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Yu, Xinwei. "Immunoglobulin G N-glycan profiling as a risk stratification biomarker for type 2 diabetes." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2019. https://ro.ecu.edu.au/theses/2199.
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Objective
Type 2 diabetes (T2DM) is a complicated and comprehensive disease that has many metabolic facets with its prevalence increasing with age. The inflammation hypothesis of T2DM was proposed at the American Diabetes Association’s 65th scientific session and subsequently validated in many studies. Immunoglobulin G (IgG) is the main component of antibody formation after a secondary immune response and therefore plays an important role in the inflammation cascade and in the occurrence and development of age-related diseases. N-glycosylation, an important post-translation modifying process, significantly affects the function of IgG molecules, including complement activation, receptor binding properties, molecular recognition and aggregation. As T2DM is a low-grade chronic inflammatory disease and IgG N-glycosylation involves in the inflammation cascade, we hypothesised that IgG N-glycans could be involved in pathophysiological process of T2DM. To provide clues to the molecular mechanisms, and screen intervention targets and search for early diagnosis marker of T2DM, we conducted an observational study analyzing the correlation between IgG N-glycans and aging, and age-related disease, T2DM.
Methods
This was an observational study with a longitudinal design. A community-based cohort in Beijing Xicheng district was established in 2012, and 701 participants aged from 23 to 68 (244 males and 457 females) were recruited. Demographic information and 39 clinical traits (7 anthropometric, 10 biochemical and 22 hematological) were collected and blood was sampled for plasma IgG N-glycans analysis using Ultra performance liquid chromatography (UPLC). From the glycan testing platform, 22 IgG N-glycan chromatographic peaks were detected and then 22 basic glycan traits (GP1-2, GP4-19, GP21-24) were calculated from the relative contributions of individual peaks to the total IgG N-glyans. Based on the 22 basic glycan traits, 54 derived glycan traits (17 derived basic glycan traits, 14 neutral glycan traits, 23 derived neutral glycan traits) were obtained for describing glycosylation character in details.
In 2014, a sample of 516 participants (160 males and 356 females), aged from 26 to 66 were re-investigated in a follow-up survey and the same clinical traits were collected. All the statistical analyses were performed with SPSS 23.0 and R programming language software. All reported P values were 2-sided and PN-glycans and level of fasting plasma glucose (FPG). Canonical correlation analysis (CAA) was used to determine the integrate correlation between IgG N-glycans and clinical traits. The potential of IgG N-glycans to be a biomarker of T2DM was analysed by receiver-operating characteristic (ROC) curve and decision tree methods. The relationship between IgG N-glycan traits and age was assessed by all-subsets regression, binominal regression and permutation test.
Results
1. Screening IgG N-Glycans for type 2 diabetes
A sample of 701 participants from the baseline survey was categorised into three groups according to their FPG levels: an NGR (normal glucose regulation) group (FPGN-glycans among the three groups of participants, the low level of galactosylation was found in people with high levels of FPG. The results of Spearman’s rank correlation analyses showed a decreased level of galactosylation with increasing of age. In addition, CCA indicated that IgG N-glycan traits highly correlated with the clinical traits such as age, waist circumference, waist-hip ratio, FPG, triglyceride, creatinine and urea (canonical correlations coefficient=0.662, P
A sample of 516 participants in the 2nd follow-up study was categorised into two groups according to the changes of their FPG (ΔFPG): A ΔFPG>0 group and a ΔFPG≤0 group. After comparison and correlation analysis of IgG N-glycans between the two groups, the low level of fucosylation was found in males with increased level of FPG (P
2. Association between IgG N-glycans and chronological and biological ages
As the correlation between IgG N-glycans and FPG altered with age, and age accounted for the largest canonical loading among risk factors of T2DM, we investigated the patterns of changes in IgG glycan profiles associated with age by analyzing IgG glycosylation in 701 community-based Han Chinese. Nineteen IgG N-glycan traits, including glycan peaks (GP) GP1, 2, 4-15, 17-19, 21, 23, change considerably with age and specific combinations of these glycan features, named “glycan age”, can explain 23.3% to 45.4% of the variance in chronological age in this population. In addition, the clinical traits (FPG and aspartate aminotransferase) which associated with biological age were strongly correlated with the “glycan age”.
Conclusions
1. IgG N-glycans showed significant variability in a Chinese Han population and significantly correlated with the level and the changes of FPG and other clinical traits associated with T2DM. The decision tree analysis could be appropriate in building a diagnostic model based on the IgG N-Glycan profiles to distinguish people with different FPG levels. Therefore, IgG N-glycosylation could be a potential early diagnostic biomarker of T2DM.
2. The study showed that most of IgG glycans were significantly related with chronological age in Han Chinese population and we investigated the extensive patterns of changes in IgG N-glycans with chronological age. The age predictive models consisted of 12 glycan structures and explained 23.2% to 45.4% of variance in chronological age. The remaining variance in these glycans was associated with the clinical traits related to biological age. Therefore, IgG glycosylation seems to correlate with both chronological and biological ages and thus contributes to the aging process. Models that can indicate biological age are of significant interest for prevention, diagnosis, and monitoring of aging and age-related diseases.
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Ding, Juan. "A Proteomic Approach to Identify Biomarkers for Growth Hormone and Aging." Ohio University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1250622748.
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Deziderio, Leandro Aparecido Grange. "Extração das isoformas da proteína precursora do amilóide em plasma rico em plaquetas para testes proteômicos como biomarcador da doença de Alzheimer." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/75/75132/tde-24082009-165818/.
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Este trabalho de mestrado teve como objetivo o desenvolvimento de uma metodologia analítica focada no preparo de amostra protéica. O objeto de estudo foram os fragmentos solúveis das isoformas da proteína precursora do amilóide (APPs) presentes no plasma rico em plaquetas. As APPs têm sido amplamente estudadas em diversos grupos de pesquisa no Brasil e em outros no mundo como possíveis biomarcadores para a doença de Alzheimer. O preparo de amostra é a etapa fundamental que influencia significativamente nos resultados seguintes, especialmente quando se trata de amostras protéicas que exigem maiores cuidados. Para a avaliação dos melhores preparos de amostra para as APPs, foi utilizado SDS-PAGE e eletrotransferências de proteínas por Western Blotting. A eficiência dos preparos foi avaliada baseando-se nos resultados de revelação com anticorpos específicos para APP e medidas de densitometria de bandas. Após a escolha do melhor preparo de amostra utilizando SDS-PAGE e Western Blotting, as isoformas da APP foram separadas por eletroforese bidimensional (2DE). Durante a etapa de preparo de amostra, os resultados inesperados de massa molecular, o que indicou possível biodegradação das APPs. A identificação da fonte de interferência foi realizada estudando as variáveis dos preparos de amostra. Com isso foi possível determinar a fonte de interferência, mas uma avaliação mais detalhada das isoformas (como utilização de espectrometria de massas) não foi possível.The goal of this Master\'s work was to develop an analytical methodology focused on protein sample preparation. The analyte studied were soluble amyloid precursor protein isoforms (APPs) which has been studied in many groups in Brazil and around the world as a possible biomarker for Alzheimer\'s disease. Sample preparation is a crucial step that influence significantly on next results, especially about biological samples which require more attention. For the best sample preparation for APPs, was used SDS-PAGE and protein electrotransference by Western Blotting techniques. The efficiency of the sample preparations was evaluated based on specific antibody reactions and densitometry measures of these interactions. After that, the APP isoforms were analyzed by two dimensional electrophoresis (2DE). During the sample preparation, were obtained unexpected molecular mass results, which indicated some APPs biodegradation. For the determination of the interference source, the variants steps of the sample preparation were analyzed. The sample preparation interference source was identified, but a more detailed study of the isoforms (by mass spectrometry) was not possible as well as the analysis of the identity of the possible fragmented isoforms.
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Kranawetvogl, Andreas [Verfasser], and Franz [Akademischer Betreuer] Worek. "Untersuchung neuartiger Disulfid-Addukte aus humanem Plasma als Biomarker zum Nachweis einer Vergiftung mit phosphororganischen Cholinesteraseinhibitoren / Andreas Kranawetvogl ; Betreuer: Franz Worek." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1188200631/34.
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Iguchi, Kota. "Chronological profiling of plasma native peptides after hepatectomy in pigs: Toward the discovery of human biomarkers for liver regeneration." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225465.
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Saarnio, J. (Juha). "Distribution of carbonic anhydrase IX, MN/CA IX, in normal and neoplastic gastrointestinal and hepatobiliary tissues:its potential value as a new biomarker and comparison of its expression with that of isoenzymes I, II, IV, V, and VI." Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514257901.
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Abstract
The carbonic anhydrase (CA) gene family contains eleven active members, the basic physiological functions of which are linked to the interconversion of carbon dioxide and bicarbonate (CO2 + H2O ⇔ H+ + HCO3⇔ H2CO3-). They participate in a variety of physiological processes that involve pH regulation, CO2 and HCO3- transport and water and electrolyte balance, and some new functions have also been suggested recently. A novel tumour-associated antigen, MN, containing a CA-domain and named MN/CA IX, has been found to promote cell proliferation when transfected into NIH3T3 cells and has also been shown to be a potential biomarker for neoplasia in the uterine cervix.
The present study examines the expression of MN/CA IX in the normal alimentary tract by immunohistochemistry and compares it with the expression of cytoplasmic CA I, CA II, apical plasma membrane associated CA IV and secretory CA VI. The distribution of mitochondrial CA V is examined by immunohistochemistry and Western blotting. The value of MN/CA IX as a potential biomarker of gastrointestinal tumours is assessed in a series of colorectal and hepatobiliary neoplasms.
A positive immunoreaction for MN/CA IX was detected in the basolateral plasma membrane of the gastric, intestinal and biliary epithelium, but was confined to the proliferating cryptal enterocytes in the human gut, suggesting a role in cellular proliferation. In colorectal tumours, MN/CA IX immunoreaction was also located in the proliferative zone, indicating that it could be a useful marker of cellular proliferation. In the case of hepatobiliary tumours a positive signal was mainly associated with tumours of biliary epithelial parentage.
These results demonstrate that MN/CA IX has a unique expression pattern in the alimentary tract relative to other CAs. Its localization and enzymatic properties suggest that it may have a dual function in the gastrointestinal epithelium. Through its CA activity it could participate in the regulation of carbon dioxide/bicarbonate homeostasis, while its localization to the basolateral surfaces of proliferating cryptal enterocytes suggests that it may serve as a ligand or receptor for one or more other proteins that regulate intercellular communication and/or cell proliferation. MN/CA IX may also serve as a new biomarker of gastrointestinal tumours.
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Byström, Sanna. "Affinity assays for profiling disease-associated proteins in human plasma." Doctoral thesis, KTH, Proteomik och nanobioteknologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-202616.
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Affinity-based proteomics offers opportunities for the discovery and validation of disease-associated proteins in human body fluids. This thesis describes the use of antibody-based immunoassays for multiplexed analysis of proteins in human plasma, serum and cerebrospinal fluid (CSF). This high-throughput method was applied with the objective to identify proteins associated to clinical variables. The main work in this thesis was conducted within the diseases of multiple sclerosis and malignant melanoma, as well as mammographic density, a risk factor for breast cancer. The suspension bead array (SBA) technology has been the main method for the work presented in this thesis (Paper I-IV). SBA assays and other affinity proteomic technologies were introduced for protein profiling of sample material obtained from clinical collaborators and biobanks. Perspectives on the validation of antibody selectivity by means of e.g. immuno-capture mass spectrometry are also provided. Paper I describes the development and application of a protocol for multiplexed pro- tein profiling of CSF. The analysis of 340 CSF samples from patients with multiple sclerosis and other neurological disease revealed proteins with potential association to disease progression (GAP43) and inflammation (SERPINA3). Paper II continued on this work with an extended investigation of more than 1,000 clinical samples and included both plasma and CSF collected from the same patients. Comparison of disease subtypes and controls revealed five plasma proteins of potential diagnostic relevance, such as IRF8 and GAP43. The previously reported associations for GAP43 and SERPINA3 in CSF was confirmed. Subsequent immunohistochemical analysis of post-mortem brain tissue revealed differential protein expression in disease affected areas. In Paper III, 150 serum samples from patients with cutaneous malignant melanoma were analyzed. Protein profiles from antibody bead arrays suggested three proteins (RGN, MTHFD1L, STX7) of differential abundance between patients with no disease recurrence and low tumor thickness (T-stage 1 and 2) compared to patients with high tumor thickness (T-stage 3 and 4) and disease recurrence. We observed MTHFD1L expression in tissue of a majority of patients, while expression of STX7 in melanoma tissue had been reported previously. Paper IV describes the analysis of protein in plasma in relation to mammographic breast density (MD), one of the strongest risk factors for the development of breast cancers. More than 1,300 women without prior history of breast cancer were screened. Linear associations to MD in two independent sample sets were found for 11 proteins, which are expressed in the breast and involved in tissue homeostasis, DNA repair, cancer development and/or progression in MD. In conclusion, this thesis describes the use of multiplexed antibody bead arrays for protein profiling of serum, plasma and CSF, and it shortlists disease associated proteins for further validation studies.QC 20170302
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Klein, Katharina [Verfasser], and Frank [Akademischer Betreuer] Kolligs. "Prognostische und therapeutische Rolle von HPP1 als molekularer Biomarker im Plasma von Patienten mit metastasiertem kolorektalem Karzinom / Katharina Klein ; Betreuer: Frank Kolligs." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1206096454/34.
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Logeeshan, Velmanickam. "Implementation of Low Cost, High-Throughput and High Sensitive Biomarker Detection Technique in Serum/Plasma Samples by Integrating Dielectrophoresis and Fluorescence Based Platform." Diss., North Dakota State University, 2019. https://hdl.handle.net/10365/29893.
Full textAbstract:
Low-cost, highly-sensitivity, and minimally invasive tests for the detection and monitoring of life-threatening cancers can reduce the worldwide disease burden. The disease diagnosis community is constantly working to improve the detection capabilities of the deadly cancers (e.g.: pancreatic and lung) at their early stages. Still there were many cancers cannot be detected at their early stages due to lack of early diagnosis techniques. One of the reason being, many cancers that occur in the body release minute amounts of biomarker molecules during the initial stages (e.g.: DNA, RNA, miRNA and antigens) in the body fluids such as blood and serum. Since the traditional bio-sensing techniques have reached their maximum capacity in terms of critical performance parameters (sensitivity, detection time, reproducibility and limit of detection) there is an urgent need for innovative approaches that can fill this gap.
To address this unmet need, here we report on developing a novel bio-sensing technique for detecting and quantifying biomolecules from the patients? plasma/serum samples at point-of-care settings. Here we have investigated the novel interactions between biomolecules and externally applied fields to effectively manipulate and specifically concentrate them at a certain detection spots near electrodes on the detection device. Then the near-field interactions between the fluorophores and the free electrons on metal surfaces were successfully integrated with the externally applied low frequency (<10MHz) electric field, to achieve maximum florescence enhancement, that produces the detection limit of target-biomolecules in the rage of femto molars (fM). Moreover, the externally applied electric potential produces dielectrophoretic and thermophoretic force on the biomolecules, together with these forces we were able to separate the fluorophore-labelled rare target-biomolecules from the others in a sample.
The novel integrated technique is tested and proved to be superior to the current gold standards (qRT-PCR and ELISA) for target-biomolecules detection in critical performance parameters. Finally the technique was used to analyze healthy and pancreatic cancer patients? samples and further it has been proved that we can differentiate the healthy individuals and cancer patients. In addition, this technique is being applied to the other diseases such as obesity, opioid addiction and other types of cancers.
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Laube, Heli [Verfasser]. "Plasma VEGF-Konzentration als Biomarker eines kompetenten Brain-pulls: seine Veränderungen nach Mahlzeit- und CRH-Stimulation bei normalgewichtigen und adipösen Probanden / Heli Laube." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2011. http://d-nb.info/1015756883/34.
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Giebel, Gerald Kraft Max Ernst [Verfasser], and Marcus [Akademischer Betreuer] Unger. "Quantitative Analyse von neuroendokrinen Peptiden als potentielle Biomarker im Liquor und Plasma von Parkinson Patienten und Kontrollpersonen / Gerald Kraft Max Ernst Giebel ; Betreuer: Marcus Unger." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2017. http://d-nb.info/1173163131/34.
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Serra, Matamala Isabel. "Estudi del perfil proteic del plasma de pacients amb diferents graus d’hepatopatia: identificació de biomarcadors del carcinoma hepatocel·lular." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/381070.
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El carcinoma hepatocel.lular (CHC) és la principal causa de mort en pacients cirròtics. Per aquesta raó, aquests pacients s’inclouen en un programa de vigilància amb una ecografia semestral per tal de detectar el CHC en un estadi precoç, quan la curació és possible. Tot i això, només un 40% dels casos es diagnostiquen en un estadi inicial i la taxa de recidiva després del tractament curatiu (resecció quirúrgica o ablació percutània) és molt elevada. Per això, és tan important la identificació de biomarcadors serològics com a eina complementària per la vigilància i per tal de predir la recidiva tumoral després del tractament. L’objectiu principal d’aquesta tesi és l’anàlisi del perfil proteic del plasma de pacients cirròtics amb i sense CHC per identificar biomarcadors diagnòstic inicial de marcadors i malaltia disseminada.
Es va analitzar el perfil proteic de 30 mostres de plasma de procedents de 12 pacients amb diferents graus d’hepatopatia crònica (fibrosi moderada n=3, cirrosi compensada Child Pugh A n=7, cirrosi descompensada Child Pugh B n=2), 15 pacients cirròtics amb CHC (BCLC 0/A, n=9; BCLC C/D amb trombosi portal tumoral i/o metàstasi n=6) i 3 voluntaris sans sense malaltia hepàtica. Es van deplecionar les 20 proteïnes majoritàries del plasma i abans de la digestió enzimàtica es va realitzar un pre-fraccionament del plasma amb electroforesi unidimensional. Posteriorment es va fraccionar la mostra per cromatografia líquida d’alta resolució acoblada a un espectròmetre de masses en tàndem per la seqüenciació peptídica (HPLC-MS/MS).
Es va identificar un panel de 31 biomarcadors diagnòstic de CHC inicial al comparar el perfil proteic de mostres de pacients cirròtics amb CHC inicial vers pacients cirròtics sense CHC; i un panell de 41 biomarcadors de disseminació tumoral de CHC al comparar pacients amb CHC avançat vers CHC inicial. Es van detectar tres vies de senyalització activades a partir de l’anàlisi Ingenuity Pathway Analysis, observant una activació de la via de resposta aguda i de la via de producció d’òxid nítric en pacients amb CHC, i la via de senyalització LXR/RXR fortament activada relacionada amb la malaltia tumoral disseminada. A més les proteïnes plasmàtiques identificades en pacients amb CHC avançat disseminats van predir l’activació de MYC, VEGF, HGF i HNF1A com a reguladors upstream. És interessant destacar que el 79% del biomarcadors identificats ja s’han relacionat anteriorment en altres càncers i /o CHC. Finalment es van validar els nivells de 2 de 7 biomarcadors candidats seleccionats per la técnica enzyme-linked immunosorbent assays (ELISA). En conclusió, a partir de l’anàlisi proteòmic del plasma vam ser capaços d’identificar un panell de biomarcadors diagnòstic de CHC. Una vegada validats aquest marcadors en una cohort més àmplia independent, el panell proposat podrà utilitzar-se com una eina per millorar el maneig dels pacients amb CHC i així millorar la seva supervivència.Hepatocellular carcinoma (HCC) is the main cause of death in cirrhotic patients. For that reason, these patients are included in a surveillance program with abdominal ultrasonography twice per year to detect HCC at early tumour stages, when cure is highly likely. Nevertheless, only 40% of the cases are diagnosed at early stages and the HCC recurrence rate after curative treatment -surgical resection or percutaneous ablation- is very high. Therefore, the identification of biomarkers is needed to use them as complementary tools for surveillance and for predicting tumour recurrence after treatment. The main aim of this thesis is to perform proteomic profiling of the plasma of cirrhotic patients with and without HCC to identify diagnostic and invasiveness biomarkers. We analysed the protein profile of 30 plasma samples from 12 selected liver disease patients with different grade of fibrosis (mild fibrosis n=3, cirrhotic Child-Pugh A n=7 and Child-Pugh B n=2), 15 HCC patients (BCLC 0/A, n=9; BCLC C/D with portal thrombosis and/or metastasis, n=6) and 3 healthy voluntaries. Plasma samples were depleted of 20 most abundant interfering proteins fractionated by unidimensional electrophoresis and enzymatically digested, and peptides were analysed by liquid chromatography coupled with mass spectrometry (HPLC-MS/MS). We identified a panel of 31 early diagnostic biomarkers by comparing the plasma proteome of cirrhotic patients with early HCC versus those without HCC and a panel of 41 biomarkers related to tumour invasiveness HCC as compared to early cases. Pathway analysis of the differentially proteins by Ingenuity Pathway Analysis revealed vital canonical pathways involving acute phase response and nitric oxide production signalling and LXR/RXR activation specially in advanced HCC. Furthermore, differentially plasma proteins in advanced HCC suggest activation of MYC, VEGF, HGF and HNF1A as upstream regulators. Interestingly, 79% of identified biomarkers have been already reported in HCC and other cancer. Finally we validate the plasma levels of 2 out 7 biomarker candidates selected by enzyme-linked immunosorbent assays (ELISA). In conclusion we have been able to identify a panel of diagnostic and prognostic biomarkers of HCC by plasma protein analysis. Once validated in an independent cohort, our plasma-based biomarker panels could be used as complementary tools to improve the clinical management of HCC patients.
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Neiman, Maja. "Bead based protein profiling in blood." Doctoral thesis, KTH, Proteomik, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-117960.
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This thesis is about protein profiling in blood-derived samples using suspension bead ar- rays built with protein affinity reagents, and the evaluation of binding characteristics and potential disease relation of such profiles. A central aim of the presented work was to discover and verify disease associated protein profiles in blood-derived samples such as serum or plasma. This was based on immobiliz- ing antigens or antibodies on color-coded beads for a multiplexed analysis. This concept generally allow for a dual multiplexing because hundreds of samples can be screened for hundreds of proteins in a miniaturized and parallelized fashion. At first, protein antigens were used to study humoral immune responses in cattle suffering from a mycoplasma infec- tion (Paper I). Here, the most immunogenic of the applied antigens were identified based on reactivity profiles from the infected cattle, and were combined into an antigen cocktail to serve as a diagnostic assay in a standard ELISA set-up. Next, antibodies and their em- ployment in assays with directly labeled human samples was initiated. This procedure was applied in a study of kidney disorders where screening of plasma resulted in the discovery of a biomarker candidate, fibulin-1 (Paper II). In parallel to the disease related applica- tions, systematic evaluations of the protein profiles were conducted. Protein profiles from 2,300 antibodies were classified on the bases of binding properties in relation to sample heating and stringent washing (Paper III). With a particular focus on heat dependent de- tectability, a method was developed to visualize those proteins that were captured to the beads in an immunoassay by using Western blotting (Paper IV). In conclusion, this thesis presents examples of the possibilities of comparative plasma profiling enabled by protein bead arrays.QC 20130208
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Monteiro, Anita-Ann. "Detection of exosomal mirna from different volumes of biofluids as biomarkers for the diagnosis of sepsis : Future diagnostics of sepsis." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-17592.
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Sepsis, a life-threatening condition which results from a dysregulation of host response to infection and leads to multiple organ dysfunction, is a cause for great concern. The current gold standard of detection – Blood culturing – is a highly time-consuming process and so, research has proposed the use of biomarkers. Current biomarkers, C-reactive protein and Procalcitonin, though good indicators, individually show certain limitations with respect to the specificity and sensitivity. Hence, as a step forward from singleplex biomarkers, the development of a multi-marker panel was suggested. For this purpose, the use of microRNAs (miRNAs) were employed to serve as potential biomarkers for the detection of sepsis. The aim of this study was to determine whether a higher concentration of miRNA would be obtained from a larger volume of plasma as well as to see if the miRNA present in blood can be used for the diagnosis of sepsis. Extractions were carried out using the QIAGEN exoRNeasy Plasma: Midi & Maxi Kits from plasma and Norgen’s Total RNA Purification Kit from blood. The samples were analysed and quantified using the Qubit® microRNA assay kit & Qubit® 3.0 Fluorometer and the NanoDrop™ 2000 Spectrophotometer. Statistical analysis of the results revealed that there was a significant difference between miRNA concentrations in the two volumes of plasma analysed. Based on the accurate Qubit measurements and readings, it was concluded that a larger volume of plasma, does yield a higher concentration of miRNA. In addition, it was also established that the miRNA detected in blood, could be used as probable biomarkers for the diagnosis of sepsis.
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Hubel, Silvia [Verfasser]. "Untersuchung der Biomarker Interferon-gamma induziertes Protein 10 (IP-10) und CXC-Motiv-Chemokinrezeptor 3 (CXCR3) im Plasma nierentransplantierter Patienten in den ersten fünfzehn Monaten nach Transplantation / Silvia Hubel." Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1218073640/34.
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Farthing, Don E. "INVESTIGATION OF INOSINE AND HYPOXANTHINE AS BIOMARKERS OF CARDIAC ISCHEMIA IN PLASMA OF NON-TRAUMATIC CHEST PAIN PATIENTS AND A RAPID ANALYTICAL SYSTEM FOR ASSESSMENT." VCU Scholars Compass, 2008. http://hdl.handle.net/10156/1510.
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Dubois, Christelle. "Confirmation de biomarqueurs pour le pronostic du sepsis et développement de tests rapides High plasma level of S100A8/S100A9 and S100A12 at admission indicates a higher risk of death in septic shock patients Top-down and bottom-up proteomics of circulating S100A8/S100A9 complexes in plasma of septic shock patients." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS521.
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Le sepsis est la 3eme cause de mortalité dans les pays occidentaux, avec un taux de mortalité entre 20 et 50% selon la sévérité. La « prédiction » du devenir clinique du patient est essentielle pour établir le traitement le plus adéquat. Quelques protéines marqueurs de l'inflammation ou d'une infection (CRP, procalcitonine) sont citées pour le suivi des patients en clinique mais manquent de spécificité pour le sepsis. D'autre part, les études « omiques » ont permis de générer des listes de biomarqueurs potentiels du pronostic vital du sepsis. En revanche, aucun n'a encore été validé et/ou confirmé en fonction de la gravité du sepsis et du devenir du patient. Il faut pour cela accéder non seulement à des cohortes de patients parfaitement caractérisées et également disposer de méthodes quantitatives robustes et validées. La spectrométrie de masse apporte une capacité de spécificité et de multiplexage à haut niveau qui permettait de confirmer l'intérêt d'une ou plusieurs de ces protéines dans le cas du pronostic du sepsis. Les dosages immunologiques apportent quant à eux en plus de la sensibilité et de la spécificité, une mise en œuvre en routine clinique simple et rapide. Dans un premier temps, une liste de biomarqueurs identifiés avec des cohortes de patients a été établie d’après la littérature. Puis, des méthodes de quantification de ces biomarqueurs ont été développées. Nous nous sommes intéressés d’une part à quantifier les calgranulines dans le plasma en développant des ELISA et des méthodes de spectrométrie de masse par des approches bottom-up et top-down. D’autre part, deux méthodes de quantification multiplexes ont été développées par spectrométrie de masse avec et sans étape d’immunopurification en fonction des concentrations des protéines présentes dans le plasma afin de vérifier la pertinence de la liste de biomarqueurs potentiels. Toutes ces méthodes ont été appliquées à une cohorte de 49 patients atteints de choc septiqueSepsis is the 3rd leading cause of death in Western countries, with a mortality rate between 20 and 50% depending on the severity. The 'prediction' of the patient's clinical outcome is essential to establish the most appropriate treatment. Some inflammation or infection markers protein (CRP, procalcitonin) are cited for clinical follow-up of patients but lack specificity for sepsis. On the other hand, "omics" studies have generated lists of potential biomarkers of sepsis prognosis. However, none have yet been validated and/or confirmed based on the severity of the sepsis and the patient's fate. This requires access not only to fully characterized patient cohorts but also to robust and validated quantitative methods. Mass spectrometry provides a high level of specificity and high multiplex capacity and that would allow to confirm the interest of one or more of these proteins for sepsis prognosis. Immunological assays provide, in addition to sensitivity and specificity, a simple and rapid routine clinical implementation. First, a list of biomarkers identified with patient cohorts was established from the literature. Then, methods to quantify these candidate biomarkers were developed. On the one hand, we have been interested in quantifying calgranulins in plasma by developing ELISAs and mass spectrometry methods using bottom-up and top-down approaches. On the other hand, two multiplex quantification methods by mass spectrometry with and without immunopurification step according to protein concentrations have been developed to verify the relevance of the list of potential biomarkers. All these methods were applied to a cohort of 49 patients with septic shock
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Hasanova, Reyhan. "Identification de nouveaux biomarqueurs des cancers colorectaux." Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCE017.
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Le cancer colorectal (CCR) est l'un des cancers les plus fréquents au monde avec les cancers du poumon et de la prostate. Une estimation précoce du pronostic pourrait aider à réduire la mortalité de ce cancer et l'implémentation de nouveaux biomarqueurs est devenu indispensable. Dans cette étude nous avons évalué deux molécules pour mieux caractériser et apprécier le pronostic du CCR : l'angiopoiétine-2 (Ang2) et la Mésotheline (Msln). Nous avons d'abord analysé des données transcriptomiques associés à des données de survie et collectés à partir de bases de données publiques. 1617 transcriptomes avaient été produites par des puces ADN et ont été téléchargés de la base GEO (NCBI Gene Expression Omnibus) 573 autres transcriptomes produits par RNAseq ont été extraits de la base de données du TCGA (The Cancer Genome Atlas). Nous avons ensuite réalisé des dosages plasmatiques par méthode ELISA chez 20 donneurs sains et 51 patients atteints de CRC métastatiques suivis dans le cadre d'une étude locale. Les analyses de survie pour Ang2 dans les transcriptomes ont montré qu'une expression intratumoral élevée d'Ang2 était associée à une baisse de la survie globale (OS, "Overall survival") et de la survie sans rechute (RFS, "relapse free survival") y compris chez les patients en stade localisé. Comme attendu, l'expression intratumoral d'Ang2 était associée à l'infiltration stromale et l'angiogenèse mais les analyses multivariées ont montré qu'Ang2 était bien un facteur indépendant de la survie (OS) après ajustement avec toutes les variables disponibles (incluant la classification CMS, "Consensus Molecular Subtypes"). Les dosages plasmatiques d'Ang2 chez les patients atteints de CRC métastatique ont montré que les taux d'Ang2 étaient plus élevés chez les patients que chez les donneurs et qu'un taux élevé était associé à une PFS plus basse. Une expression de Msln élevée dans les transcriptomes était associée à une survie réduite (OS et RFS). C'était également un facteur de risque indépendant de la survie (OS et RFS). L'analyse des voies de signalisations a montré que l'expression de Mésotheline était associée à la voie des éxosomes. Les dosages sériques de Msln ont également montré que les taux sont plus élevés chez les patients que chez les donneurs sains. Enfin, les patients avec des valeurs plus élevées de Msln avaient une survie OS plus basse. Au total, ces résultats suggèrent qu'Ang2 et Msln sont tous deux des biomarqueurs pronostiques pour le CRC. Nous planifions maintenant de stratifier le pronostic en fonction d'une utilisation combinée de ces deux marqueursColorectal cancer (CRC) is the third most commonly diagnosed cancer after lung cancer, and prostate cancer. The early prognostic estimation could reduce the mortality and the implementation of new biomarkers is getting indispensable. In this study we investigated two molecules for better characterization and prognosis of CRC: Angiopietin2 (Ang2) and Mesothelin (Msln). We first analyzed transcriptomic and clinicopathological data of primary tumors collected from online repositories. 1617 transcriptomes had been produced by microarrays and were downloaded from NCBI Gene Expression Omnibus (GEO) and additionally 573 RNAseq transcriptomic data were collected from The Cancer Genome Atlas (TCGA) repository. Plasma ELISA assays for Ang2 and Msln were then performed in 20 healthy donors and in 51 CRC patients from a local cohort in order to validate those proteins as potential biomarkers. Ang2 survival analyses performed on transcriptomic data showed that high intratumoral Ang2 expression was associated with poor overall survival (OS) and relapse-free survival (RFS) in CRC patients with localized stages. As expected, Ang2 expression was associated with stroma infiltration and angiogenesis but multivariate analyses showed that Ang2 was an independent factor for OS after adjusting it with all available variables (including Consensus Molecular Subtypes of CRC). The plasma measurement of Ang2 showed that the metastatic CRC (mCRC) patients had higher levels than the healthy donors and the progression free survival (PFS) was lower in patients with higher Ang2. High intratumoral MSLN expression in CRC transcriptomes was associated with poor OS and RFS. It was also an independent factor for OS and RFS. Pathway analyses revealed that Msln expression was associated with tumor exosome pathway and cell invasion. ELISA measurements of Msln levels showed that the patients with colorectal cancer had significantly higher Msln levels than healthy donors. Furthermore, the CRC patients with increased levels of Msln had poor OS than the patients with low Msln levels. Taken together, these results suggest that both Ang2 and Msln are independent prognostic biomarkers for CRC. We now aim to stratify risk using both Ang2 and Msln to improve the treatment of CRC patients
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Drobin, Kimi. "Antibody-based bead arrays for high-throughput protein profiling in human plasma and serum." Licentiate thesis, KTH, Proteinvetenskap, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-225980.
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Affinity-based proteomics utilizes affinity binders to detect target proteins in a large-scale manner. This thesis describes a high-throughput method, which enables the search for biomarker candidates in human plasma and serum. A highly multiplexed antibody-based suspension bead array is created by coupling antibodies generated in the Human Protein Atlas project to color-coded beads. The beads are combined for parallel analysis of up to 384 analytes in patient and control samples. This provides data to compare protein levels from the different groups. In paper I osteoporosis patients are compared to healthy individuals to find disease-linked proteins. An untargeted discovery screening was conducted using 4608 antibodies in 16 cases and 6 controls. This revealed 72 unique proteins, which appeared differentially abundant. A validation screening of 91 cases and 89 controls confirmed that the protein autocrine motility factor receptor (AMFR) is decreased in the osteoporosis patients. Paper II investigates the risk proteome of inflammatory bowel disease (IBD). Antibodies targeting 209 proteins corresponding to 163 IBD genetic risk loci were selected. To find proteins related to IBD or its subgroups, sera from 49 patients with Crohn’s disease, 51 with ulcerative colitis and 50 matched controls were analyzed. From these targeted assays, the known inflammation-related marker serum amyloid protein A (SAA) was shown to be elevated in the IBD cases. In addition, the protein laccase (multi-copper oxidoreductase) domain containing 1 (LACC1) was found to be decreased in the IBD subjects. In conclusion, assays using affinity-based bead arrays were developed and applied to screen human plasma and serum samples in two disease contexts. Untargeted and targeted screening strategies were applied to discover disease-associated proteins. Upon further validation, these potential biomarker candidates could be valuable in future disease studies.QC 20180412
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Chu, Ling-fung, and 朱凌峯. "Plasma inflammatory biomarkers in stable COPD patients." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48333682.
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Chronic obstructive pulmonary disease (COPD) is one of the world’s most common chronic diseases, and consists of chronic bronchitis that involves chronic inflammation of the bronchi, or emphysema that involves destruction of lung alveoli. In COPD patients, the airways become narrowed, and the airflow is irreversibly obstructed. This leads to a limitation of the flow of air to and from the lungs, causing shortness of breath (dyspnea), as well as abnormal inflammatory response in the lung. Nowadays, COPD is often under-diagnosed, as spirometry was not performed until patient has significant symptoms of dyspnea, cough and sputum production. At that stage, the COPD patients may have reached an advanced stage with considerable loss of lung function. Thus, biomarkers are of great interest for research and clinical purposes in COPD, especially for early diagnosis of COPD.
In this study, the relationship between plasma levels of different biomarkers, including monocyte chemoattractant protein-1 (MCP)-1 (a primary chemoattractant biomarker), matrix metalloproteinase nine (MMP)-9, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) (injury and repair biomarkers), and growth differentiation factor 15 (GDF)-15 (a novel biomarker), in 29 healthy ever-smokers and 116 COPD patients was investigated using commercially available enzyme-linked immunosorbent assay (ELISA) kits. We also investigated the correlations between these biomarkers and lung function. There were significant increases in plasma MCP-1, MMP-9, HGF and GDF-15 in COPD patients compared to healthy smokers. Among ever-smokers with or without COPD, plasma MCP-1, MMP-9 and HGF levels were inversely correlated with force expiratory volume in one second![FEV1 (% predicted)] after adjustment for age, smoking status and packyears smoked. Correlation was also found between plasma MCP-1 and HGF, plasma MMP-9 and HGF or GDF-15, plasma HGF and GDF-15 after adjustment for age, smoking status and pack-years smoked. Further multiple linear regression analyses demonstrated that plasma MMP-9 level increased with the COPD GOLD stages.
In conclusion, our findings suggest that MMP-9 might be as an important biomarker for COPD initiation and progression. As this study provides only evidence of association rather than of causation, prospective studies are required to assess biological significance of these associations between the plasma biomarkers.published_or_final_version
Medicine
Master
Master of Medical Sciences
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Walsh, Kyle B. "Plasma Biomarkers for Ischemic and Hemorrhagic Stroke Diagnosis." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511859455574062.
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Creegan, Rhona. "Identification of plasma lipid biomarkers in Alzheimer's disease." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2014. https://ro.ecu.edu.au/theses/1340.
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Alzheimer’s disease (AD), the commonest form of dementia, is a chronic, progressive neurodegenerative disease which manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With an ageing population, there is predicted to be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Currently there is no cure for AD and while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. Attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis but provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestations develop.
Research and understanding of AD pathology has been driven in recent years by advances in technologies, enabling the precise investigation of the lipidome; the repertoire of lipid species present in cells and tissues that reflect the net effect of gene and protein expression, which in turn are influenced by the cellular environment. Lipidomic studies have identified abnormal lipid metabolism as a key component of the pathological processes which lead to the development of AD. Therefore, lipidomic studies are crucial for advancing the understanding of AD pathology and for identifying potential therapeutic targets; these studies may also facilitate biomarker discovery. Many studies have reported abnormal lipid profiles in both AD plasma and brain tissue.
This thesis investigated plasma lipid species using a “shotgun” lipidomics approach by electrospray ionisation tandem mass spectrometry (ESI/MS/MS). Additionally, Phospholipid Transfer Protein (PLTP); a protein involved in lipid metabolism was assayed using a commercial kit. The utility of these analytes as potential AD biomarkers was investigated by testing plasma samples from the highly characterised Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The study cohort comprised over 1000 participants at inception who were classified as either healthy control (n=733), mild cognitive impairment (MCI, n=125) or AD (n=204): Samples from the baseline and 18 month follow-up time points were utilised. Plasma PLTP activity levels were measured in a subset of the baseline samples (n=259). Lipid and PLTP measurements were analysed in conjunction with supplementary neuroimaging and blood biomarker data collected as part of the AIBL study.
The thesis identified significant differences in several plasma lipids between clinical classification groups, including several ceramide, sphingomyelin (SM), phosphatidylethanolamine (PE), phosphatidylcholine (PC) and plasmalogen species. Additionally, a panel of lipids was identified which could distinguish AD participants from healthy controls with a sensitivity and specificity of 80%. Plasma PLTP activity was significantly lower in AD and MCI groups compared to healthy controls, and levels correlated with plasma Aβ in all groups and cerebral Aβ in the healthy controls.
The results of this thesis validate and extend previous findings reported in the literature. The current findings provide evidence to indicate that several lipid species and PLTP show promise as potential blood biomarkers of AD. Further investigation using a targeted lipidomics platform and prospective longitudinal follow-up is warranted.
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Johnsson, Anna. "Mining for Lung Cancer Biomarkers in Plasma Metabolomics Data." Thesis, Linköping University, Biotechnology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-57670.
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Lung cancer is the cancer form that has the highest mortality worldwide and inaddition the survival of lung cancer is very low. Only 15% of the patients are alivefive years from set diagnosis. More research is needed to understand the biologyof lung cancer and thus make it possible to discover the disease at an early stage.Early diagnosis leads to an increased chance of survival. In this thesis 179 lungcancer- and 116 control samples of blood serum were analyzed for identificationof metabolomic biomarkers. The control samples were derived from patients withbenign lung diseases.Data was gained from GC/TOF-MS analysis and analyzed with the help ofthe multivariate analysis methods PCA and OPLS/OPLS-DA. In this thesis it isinvestigated how to pre-treat and analyze the data in the best way in order todiscover biomarkers. One part of the aim was to give directions for how to selectsamples from a biobank for further biological validation of suspected biomarkers.Models for different stages of lung cancer versus control samples were computedand validated. The most influencing metabolites in the models were selected andconfoundings with other clinical characteristics like gender and hemoglobin levelswere studied. 13 lung cancer biomakers were identified and validated by raw dataand new OPLS models based solely upon the biomarkers.In summary the identified biomarkers are able to separate fairly good betweencontrol samples and late lung cancer, but are poor for separation of early lungcancer from control samples. The recommendation is to select controls and latelung cancer samples from the biobank for further confirmation of the biomarkers.NyckelordLung cancer is the cancer form that has the highest mortality worldwide and inaddition the survival of lung cancer is very low. Only 15% of the patients are alivefive years from set diagnosis. More research is needed to understand the biologyof lung cancer and thus make it possible to discover the disease at an early stage.Early diagnosis leads to an increased chance of survival. In this thesis 179 lungcancer- and 116 control samples of blood serum were analyzed for identificationof metabolomic biomarkers. The control samples were derived from patients withbenign lung diseases.Data was gained from GC/TOF-MS analysis and analyzed with the help ofthe multivariate analysis methods PCA and OPLS/OPLS-DA. In this thesis it isinvestigated how to pre-treat and analyze the data in the best way in order todiscover biomarkers. One part of the aim was to give directions for how to selectsamples from a biobank for further biological validation of suspected biomarkers.Models for different stages of lung cancer versus control samples were computedand validated. The most influencing metabolites in the models were selected andconfoundings with other clinical characteristics like gender and hemoglobin levelswere studied. 13 lung cancer biomakers were identified and validated by raw dataand new OPLS models based solely upon the biomarkers.In summary the identified biomarkers are able to separate fairly good betweencontrol samples and late lung cancer, but are poor for separation of early lungcancer from control samples. The recommendation is to select controls and latelung cancer samples from the biobank for further confirmation of the biomarkers.Nyckelord
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Correia, Marta Sofia da Silva. "Identification of potential Alzheimer’s disease biomarkers in plasma using FTIR." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/13622.
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Mestrado em Biomedicina MolecularCurrent clinical AD diagnosis criteria used to identify the disorder in patients who have already overt the advanced stage of dementia. This is too late for some kind of successful disease adjustment and consequently, early recognition of AD needs to be improved. Therefore, it is really needed different approaches for discovering new AD biomarkers, such as the application of metabolomics techniques (e.g. FTIR). The potential of FTIR in the clinical field has recently received particular attention, since it uses vibration frequencies of molecules present in the analysed sample to produce a metabolic fingerprint, which is then specific for each sample. This dissertation aims to identify biochemical alterations that might be related to dementia, being possible to distinguish between control and disease groups of plasma samples, through application of FTIR methodology at the 4000-600 cm-1 spectral region. Using plasma samples makes the process being minimally invasive, with other relevant clinical advantages. Besides the collection of blood samples used in this project, the volunteers were also submitted to cognitive evaluation trough Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR), with other relevant clinical information being also collected. All the analysed samples were matched by age and sex. For a better discrimination between control and disease samples, Principal Component Analysis (PCA) was applied to spectra data at specific regions, namely 3500-2700 cm-1, 1700-1400 cm-1, and 1200-900 cm-1. This allowed to identify the main pathological changes that occurred at the biochemical level during neurodegenerative disorder development. In the former spectral region, disease samples presented a higher content of saturated lipids in relation to the unsaturated ones, which translates in a high potential brain damage. Besides, it was also noted the presence of carboxylic acids that are usually related to lipid hyperoxidation, production of reactive carbonyls and proteins structural and functional alterations. In turn, the spectral region 1700-1400 cm-1 allowed to identify differences in protein conformation between control and disease samples, and these last ones were still related with occurrence of protein aggregates. In other hand, the 1200-900 cm-1 region could be associated to cellular damage provoked by oxidative stress in disease samples. As an important note to take, FTIR analysis could have the potential to be applied in future not only for cognitive impairment diagnosis but also for identification of disease stage and prognostic evaluation, besides assessment of disease developing risk for control subjects.
Os atuais critérios clínicos de diagnóstico da doença de Alzheimer geralmente identificam a patologia apenas quando os pacientes já atingiram a fase de demência, ou seja, o estágio mais avançado da doença. Isto revela-se demasiado tarde para que qualquer tipo de terapêutica seja bem-sucedida e, consequentemente é necessário desenvolver uma metodologia de diagnóstico que permita um reconhecimento mais precoce da doença. Desta forma, é preciso adotar diferentes abordagens para a descoberta de novos biomarcadores para a doença de Alzheimer, tais como a utilização de técnicas de metabolómica (ex. FTIR). O potencial do FTIR no campo clínico recebeu recentemente particular atenção, sendo que esta técnica utiliza as frequências de vibração das moléculas presentes na amostra analisada para produzir uma “impressão digital” metabólica, a qual é específica para cada amostra. Esta dissertação tem como objetivo a identificação de potenciais alterações bioquímicas que possam estar relacionadas com demência, tornando possível a distinção entre grupos controlo e de doentes no seio do conjunto de amostras de plasma analisadas. A utilização de amostras de plasma torna o processo minimamente invasivo, de entre outras vantagens clínicas. Para além da colheita das amostras de sangue utilizadas neste projeto, os voluntários foram submetidos a uma avaliação cognitiva através da realização do MMSE e do CDR, com outra informação clínica relevante a ser também recolhida. Todas as amostras analisadas foram emparelhadas de acordo com a idade e o sexo. Para uma melhor distinção entre amostras controlo e de doentes foi aplicada a metodologia de PCA aos dados dos espectros obtidos em regiões específicas, nomeadamente em 3500-2700 cm-1, 1700-1400 cm-1, e 1200-900 cm-1. Isto permitiu identificar as principais alterações patológicas que ocorrem a nível bioquímico durante o desenvolvimento da doença neurodegenerativa. Na primeira região espectral referida, as amostras dos doentes apresentaram um maior conteúdo de lípidos saturados comparativamente aos não saturados, o que se traduz num potencial risco cerebral maior. Para além disso, foi observada a presença de ácidos carboxílicos, usualmente relacionados com hiperoxidação de lípidos, produção de carbonilos reativos e alterações estruturais e funcionais de proteínas. Por sua vez, a região espectral 1700-1400 cm-1 permitiu identificar diferenças na conformação de proteínas entre amostras controlo e de doentes, tendo estas últimas sido ainda relacionadas com a ocorrência de agregados proteicos. Por outro lado, a região 1200-900 cm-1 pôde ser relacionada com presença de danos celulares provocados por stress oxidativo nas amostras de doentes. Como importante nota a reter, a análise por FTIR pode ter o potencial para ser aplicada no futuro não apenas para diagnóstico de disfunção cognitiva, mas também para identificação do estádio da doença e realização de prognósticos, para além da avaliação do risco de desenvolvimento da doença em sujeitos controlo.
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MARTINEZ, FERNANDEZ ALMA ESTEFANIA. "ANALYSIS OF LIPID AND PROTEIN OXIDATION STATUS IN HEART FAILURE PATIENTS." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/700135.
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Increasing body of evidence supports that oxidative stress is involved systolic and diastolic myocardial dysfunction in HF. Indeed, it has been well established an association between cardiac remodeling (hypertrophy, apoptosis or contractile dysfunction) and oxidative stress. Hence, the identification, quantification and fully characterization of oxidized biomolecules present in the plasma of HF patients can contribute to understand the mechanisms responsible for disease development but also as biological markers. However, the classic biomarkers of oxidative stress identified in HF do not provide thorough information but report about a general oxidative stress status. For a better understanding of the pathology of HF it is needed to unveil not only protein and lipid targets of oxidative damage but also the residues undergoing the modification within the protein and the structure of the oxidation products. Analysis of all of these oxPTMs and lipid peroxidation products by mass spectrometry is extremely challenging. Indeed, oxPTMs tend to occur randomly on a number of susceptible residues and proteins, making it extremely difficult to define all protein species. Along this project, plasma samples from HF patients belonging to different NYHA groups (from class I to class IV) have been employed to identify oxidized biomolecules as potential biomarkers of HF, and eventually subjected to several plasma prefractionation strategies combined with high-throughput untargeted and targeted mass spectrometry techniques. Consequently, part of this project has been focused on the study of oxidative modifications in human serum albumin (HSA), the most abundant protein in the circulatory system, associated with HF. HSA is involved in a wide range of biological functions and, due to its long half-life and high concentration in plasma, HSA is highly sensitive to undergo oxPTMs that may lead to its functional loss, thus contributing to the progression of HF. Taking advantage of the high abundance of HSA, we relatively quantified for the first time plasma levels of cysteinylated HSA (cys-HSA) and also levels of early glycated HSA (GA), and we observed a significant increase in HF patients with respect to the healthy subjects. A positive correlation between the levels of both isoforms and HF severity was highlighted whereas the abundance of total HSA showed a tendency to decrease when raising the severity degree of HF. For a deeper characterization of GA, we elucidated for the first time the early glycation pattern of HSA associated to HF by means of the newest generation of Tribrid MS instruments. Lys233 and lys525 were observed as the two most abundant glycated amino acids (79% and 13% respectively). Considering that further modifications of GA, such as rearrangement, oxidation, polymerization, and cleavage give rise to irreversible conjugates, called advanced glycation end products (AGEs), we also aimed to unveil the plasma advanced glycation pattern associated to HF. In this case, lys20, arg98, and lys402 emerged as the three most abundant carboxymethylated residues. Therefore, the results suggested that on one hand lys233 and lys525, and on the other lys20, arg98 and lys402, might represent the main potential therapeutic targets to reduce GA and AGE-HSA levels in HF patients, respectively. Besides the study of oxidized isoforms of HSA, we also tried to identify other less abundant advanced glycation and lipoxidation end products (AGEs and ALEs) in plasma by means of an enrichment strategy based on the ability of RAGE receptor to bind AGEs and ALEs. Due to the relevance of HSA in circulation, we have also evaluated the potential causal role of GA in the etiopathogenesis of HF. Hence, we pursued to evaluate the biological effects of GA on cardiac myocytes. Results highlighted that GA modulates in vitro the cardiomyocyte expression of inflammatory cytokines such as IL-6 or TNF-α. Furthermore, we reported that GA induces oxidative stress and oxidative modifications of a multitude of cellular proteins within cardiac myocytes. In addition, GA modulates the secretion of several cardiac proteins involved in response to stress biological processes. On the other hand, lipids play a crucial role in physiological processes and phospholipid disruption may participate in cardiovascular disease events, therefore the phospholipidome profiling has emerged as a powerful tool to explore novel biomarkers and mechanisms in several pathologies. Hence, we have also studied for the first time the plasma phospholipidome of HF patients. In this pilot study, we have applied both untargeted and targeted (MRM) strategies together with fractionating methods to separate the phospholipid content from the rest of plasma components, in order to decrease the heterogeneity and complexity of this biological matrix. The results suggested that HF plasma phospholipid signatures were gender-specific. In the case of females, several PE species were more abundant in HF than in the control group. On the contrary, male HF patients mainly showed a higher abundance of LPC species when compared to the male control group. Additionally, lipidomic approaches (LC-MS/MS and PRM) have been carried out to define for the first time a circulating oxidative lipid pattern associated with HF. In this case, we have focused on long- and short-chain products of lipid peroxidation since their identification and characterization in the pathology of HF were still lacking. Promising results have been pinpointed so far: we have detected 9 lipid peroxidation products (full-chain oxidized lipids together with fragmented species). In conclusion, the results gathered along this Ph.D. project provide evidence at the molecular level of the mechanisms associated to oxidative stress and oxidative damage underlying the development and progression of HF, thus contributing to a better understanding of the pathology. Indeed, the elucidation of specific modified residues within key circulating proteins such as HSA, or the characterization of long- and fragmented-chain lipid peroxidation products present in HF plasma samples reported in this thesis may pave the way to new therapies to reduce and treat HF. We have also contributed to expand the awareness of the biological effects of GA in the cardiac context. Additionally, this project has pointed out a gender-dependent adaptation of the plasma phospholipidome occurring in the pathology of HF, highlighting that gender is a major and often underestimated factor that should be carefully considered when screening lipidomes or proteomes of pathological processes. Finally, we have demonstrated that either proteomic or lipidomic technologies can provide deep biological insight into human health and disease.
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Howard, James W. "The development of mass spectrometry-based methodologies for the high throughput quantitation of peptides in biological matrices." Thesis, Loughborough University, 2018. https://dspace.lboro.ac.uk/2134/32454.
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The aim of this research was the development of mass spectrometry-based methodologies for the high-throughput quantitation of peptides in biological matrices. Glucagon and GLP-1, which are of interest as biomarkers and in the development of therapeutics, were chosen as model peptides. Immunoassays that are traditionally used to quantify these often perform poorly; therefore, necessitating the development of alternative methodologies. Application of mass spectrometry-based methodologies to these analytes has, however, been limited, primarily due to sensitivity challenges, but also due to analytical challenges associated with their endogenous nature and instability in biological matrices. Chapter 2 describes the development and qualification of the first liquid-chromatography coupled tandem mass spectrometry (LC-MS/MS) method for the quantitation of endogenous glucagon from human plasma. A novel 2D extraction procedure was developed to ensure robustness and sensitivity, whilst a novel surrogate matrix quantitation strategy took into account the endogenous nature of the analyte. A lower limit of quantitation (LLOQ) of 25 pg/mL was qualified, which was a considerable improvement over that previously reported in the literature (250 pg/mL) for a LC-MS/MS method. Clinical samples were cross-validated against a conventional radioimmunoassay (RIA), and similar pharmacokinetic (PK) profiles resulted, demonstrating that the methods were complementary. In Chapter 2 glucagon instability in biological matrix was noted. To characterise this further, in Chapter 3 in vitro glucagon metabolites were identified using high-resolution mass spectrometry (HRMS). Metabolites observed by others (glucagon19-29, glucagon3 29 and [pGlu]3glucagon3 29) in alternative matrices were identified, alongside novel metabolites (glucagon20-29 and glucagon21-29). Cross-interference of these metabolites in immunoassays may help to explain their poor performance, whilst knowledge of metabolism may also aid the development of future stabilisation strategies. The method developed in Chapter 2 was refined in Chapter 4 to improve sensitivity, robustness and throughput, and to add GLP-1 as a secondary analyte. The sensitivity achieved (glucagon: 15 pg/mL LLOQ, GLP-1: 25 pg/mL LLOQ) is the highest reported for both peptides for an extraction avoiding immunoenrichment. Specificity of endogenous glucagon quantitation was assured using a novel approach with a supercharging mobile phase additive to access a sensitive qualifier transition. A cross-validation against established immunoassays using physiological study samples demonstrated some similarities between the methods. Differences between the immunoassay results exemplified the need to develop alternative methodologies. The resulting LC-MS/MS method is considered a viable alternative to immunoassays, for the quantitation of endogenous glucagon, dosed glucagon and/or dosed GLP-1 in human plasma.
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de, Cal Massimo. "Sepsis and AKI in ICU Patients: the role of Plasma Biomarkers." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3421725.
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Sepsis is a primary cause of morbidity and mortality in intensive care unit (ICU) and critically ill patients. Gram-negative bacteria are implicated in 50-60% of cases of sepsis in ICU and endotoxin is considered to play an important role in the pathogenesis of septic shock.
Sepsis is also a contributing factor in more than 20% of cases of acute kidney injury (AKI) in ICU patients, with cases severe enough to require renal replacement therapy. AKI occurs in 35-65% of ICU admissions and most studies show a threefold to fivefold increase in the risk of death among patients with AKI compared to patients without AKI.
Given the higher mortality rate of ICU patients with sepsis and AKI, we decided to investigate the possible correlation between serum biochemical markers of organ damage, such as Neutrophil Gelatinase-Associated Lipocalin (NGAL), Advanced Oxidation Protein Products (AOPP) and Brain Natriuretic Peptide (BNP) and endotoxin activity in ICU septic patients. Moreover, comparisons of the levels of these biomarkers were made between septic and non septic patients, septic patients with or without AKI and between patients who developed AKI with or without sepsis.
Ninety-eight consecutive adult patients admitted to ICU of San Bortolo Hospital, Vicenza, Italy, between October 2008 and August 2010, were enrolled in this study. Patients were divided in two groups depending on the presence of sepsis, defined as Systemic Inflammatory Response Syndrome (SIRS) associated with an infectious process. Fifty-six patients had sepsis, while forty-two patients were non septic. Among septic patients, twenty-four subjects developed AKI, defined by RIFLE criteria, while thirty-two did not. AKI occurred in fourteen patients without sepsis as well.
A significant correlation (p=0.02) was found only between endotoxin activity and BNP levels of septic patients. The levels of NGAL, BNP and AOPP were significantly higher among septic patients compared with non septic subjects (p<0.001). Among septic patients, subjects who developed AKI showed significant higher levels of NGAL and AOPP (p=0.0425), and BNP (p=0.0327). Among patients who developed AKI, a significant difference was found only in terms of AOPP levels between septic and non septic patients.
The correlation between endotoxin activity and BNP in septic patients and the increase in the levels of NGAL, BNP and AOPP in case of sepsis and AKI, in particular if they are associated, indicate a multiorgan involvement in these two conditions. Their evaluation can allow clinicians to individualize earlier patients at higher risk of morbidity and mortality.La sepsi è una delle cause principali di morbidità e mortalità nei pazienti critici in Terapia Intensiva. I batteri Gram-negativi sono implicati nel 50-60% dei casi di sepsi in Terapia Intensiva e l’endotossina svolge un ruolo importante nella patogenesi dello shock settico. La sepsi è anche un fattore che contribuisce in oltre il 20% dei casi al danno renale acuto nei pazienti in terapia intensiva, e in alcuni casi vi è la necessità di una terapia renale sostitutiva. L’insufficienza renale acuta (IRA) si verifica nel 35-65% dei ricoveri in Terapia Intensiva e la maggior parte degli studi mostrano un aumento di cinque volte sul rischio di morte tra i pazienti con danno renale acuto rispetto ai pazienti senza IRA. Dato il tasso di mortalità più elevato di pazienti in Terapia Intensiva con sepsi e IRA, si è indagato nei pazienti settici della Terapia Intensiva sulla possibile correlazione tra i biomarcatori di danno d'organo (NGAL, AOPP e BNP) e l'attività dell’endotossina. Inoltre, il confronto dei livelli di questi marcatori sono stati analizzati tra i pazienti settici e non settici, pazienti settici con o senza IRA e tra i pazienti che hanno sviluppato danno renale acuto, con o senza sepsi. Novantotto pazienti adulti ricoverati in Terapia Intensiva dell'Ospedale di San Bortolo, Vicenza, Italia, tra ottobre 2008 e agosto 2010, sono stati arruolati in questo studio. I pazienti sono stati divisi in due gruppi a seconda della presenza di sepsi, definita come Sindrome da Risposta Infiammatoria Sistemica (SIRS) associata a un processo infettivo. Cinquantasei pazienti presentavano sepsi, mentre 42 pazienti non presentavano sepsi. Tra i pazienti settici, 24 soggetti hanno sviluppato IRA, definita dai criteri RIFLE, mentre 32 non hanno IRA. Una correlazione significativa tra l’attività di endotossina e i biomarcatori è stata trovata solo con i livelli di BNP dei pazienti settici (p=0,02). I livelli di NGAL, BNP e AOPP erano significativamente più alti tra i pazienti settici rispetto ai soggetti non settici (p<0,001). Tra i pazienti settici, i soggetti che hanno sviluppato IRA hanno mostrato livelli più alti di NGAL e AOPP (p=0,0425), e BNP (p=0,0327). La correlazione tra l'attività dell’endotossina e i livelli di BNP nei pazienti settici, e l'aumento dei livelli di NGAL, BNP e AOPP in caso di sepsi e IRA, in particolare se sono associati, indicano un coinvolgimento multiorgano in queste condizioni. La loro valutazione può permettere ai medici di individuare prima i pazienti a maggior rischio di morbidità e mortalità.
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Ding, Juan. "A proteomic approach to identify biomarkers of growth hormone and aging." View abstract, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3372300.
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Seuma, Morlanes Jaime. "Analysis of protein biomarkers by inductively coupled plasma mass spectrometry linked immunoassay." Thesis, University of Sheffield, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538004.
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Xu, Haili. "Discovery And Validation Of Early Life Plasma Protein Biomarkers For Childhood Asthma." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/333486.
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Asthma is a lung disease which features chronic inflammation. Multiple genetic and environmental factors increase susceptibility and provoke episodes of asthma. However, the mechanisms responsible for asthma development are not well characterized. Although allergy is associated with asthma, it has not been shown to precede or predict asthma. To date, there are no clearly established biomarkers of asthma, reflecting our less adequate understanding of asthma pathobiology. In order to identify a plasma proteomic biomarker as an indicator that plasma constituents are altered early in childhood asthma, this study employed a high-throughput antibody array technique which simultaneously profiled relative expression of 507 proteins in human plasma samples from asthma and non-asthma groups. It was hypothesized that alterations of proteomic profiles are accompanied with asthma development. Out of 444 proteins, 4 proteins (erythropoietin, sGP130, galectin-3, and eotaxin-3) were identified with differential expression between asthma and non-asthma groups. Erythropoietin and sGP130 were validated with quantitative differences, which were consistent in direction with the findings from the antibody array, between two groups after having all 4 proteins assessed by ELISAs. Erythropoietin then was assessed for its biological effects in in vivo and in vitro models. It was hypothesized that EPO has influences on acetylcholine-induced airway resistance in animals and on cytokine production from peripheral blood mononuclear cells. EPO's inhibitory effect on IL-2 production and its excitatory effect on IL-6 production were demonstrated; however, the inhibitory effect of EPO on increases in airway resistance in animals was not evident. The results here suggested that asthma has identifiable components in the circulation; these plasma biomarkers may develop via distinct pathways. The demonstrated EPO's capacity of influencing on cytokine production from human immune cells, together with its systemic involvement in asthma, may reveal new opportunities for therapeutics and insights into pathogenesis of asthma.
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Murata, Koichi. "Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis." Kyoto University, 2013. http://hdl.handle.net/2433/174785.
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Encarnação, Joana. "Impact of coffee-consuming habits on plasma biomarkers in a healthy adult population." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/9707/.
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Increasing epidemiological evidence for the beneficial health effects of (poly)phenol-rich products has led to a growing interest in the role of (poly)phenols in reducing the incidence of chronic diseases. Coffee is a major contributor to dietary chlorogenic acids. However, the majority of these, unlike free phenolic acids, first need to be cleaved in order to be absorbed and about 70 % of them reach the colon intact where they are processed by the microbiota population. First, the analysis of major free phenolic acids in five commercially available soluble coffees is described. The influence of roasting and decaffeination and the contribution of free phenolic acids to the appearance of derived metabolites in plasma resulting from a pre-colonic absorption are then assessed. The hypothesis was that, as reported for chlorogenic acids, both roasting and decaffeination would have a negative impact on the quantified compounds. The contribution of free phenolic acids to the appearance of derived pre-colonic metabolites in plasma was hypothesized to be significant, as these are easily absorbed in the gastrointestinal tract. Results indicated that roasting and decaffeination reduce the amount of hydroxycinnamic acids, which in the amounts consumed with a regular coffee beverage do not significantly contribute to the early appearance of derived metabolites. The hydrolysis of 5-O-caffeoylquinic acid and 3-O-caffeoylquinic acid is a likely major contributing mechanism to the early appearance of derived metabolites in plasma. In a second stage, the impact of habitual consumption of popular (poly)phenol-rich products on human health and the impact of habitual consumption of coffee on the absorption and metabolism of chlorogenic acids were assessed in an observational human study with 62 healthy adult participants. The health status of the study population was assessed by the quantification of selected biomarkers of health using optimized methods, which were based on published protocols. The major hypotheses in this second section were that the metabolism of the biomarkers was stable over the study period (i.e. max 16 weeks); that subjects with a higher regular consumption of (poly)phenol-rich products have a healthier profile of biomarkers and that subjects with a higher absorption of coffee (poly)phenols have a healthier profile of biomarkers. A healthy and overall stable metabolism of the quantified inflammation and cardiovascular biomarkers (i.e. total aminothiols, glucose, insulin and uric acid) over a period of at least 8 - 16 weeks was confirmed. Subjects with a higher consumption were more likely to also be higher consumers of other (poly)phenol-rich products. A higher consumption of (poly)phenol-rich products was not associated with a better inflammatory and cardiovascular health profile, but the a higher presence of two colonic metabolites (i.e. vanilloylglycine and feruloylglycine) was associated with higher levels of glutathione. Overall, the results suggested a reduced bioavailability of chlorogenic acids with a higher habitual consumption of coffee including associated (poly)phenols, and encourage future investigations targeting the colonic microbiota populations.
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Qundos, Ulrika. "Antibody based plasma protein profiling." Doctoral thesis, KTH, Proteomik och nanobioteknologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-126270.
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This thesis is about protein profiling in serum and plasma using antibody suspension bead arrays for the analysis of biobanked samples and in the context of prostate cancer biomarker discovery. The influence of sample preparation methods on antibody based protein profiles were investigated (Papers I-III) and a prostate cancer candidate biomarker identified and verified (Papers III-V). Furthermore, a perspective on the research area affinity proteomics and its’ employment in biomarker discovery, for improved understanding and potentially improved disease diagnosis, is provided. Paper I presents the results of a comparative plasma and serum protein profiling study, with a targeted biomarker discovery approach in the context of metabolic syndrome. The study yielded a higher number of significant findings and a low experimental variability in blood samples prepared as plasma. Paper II investigated the effects from post-centrifugation delays at different temperatures prior sample storage of serum and plasma samples. Minor effects were found on the detected levels of more than 300 predicted or known plasma proteins. In Paper III, the detectability of proteins in plasma was explored by exposing samples to different pre-analytical heat treatments, prior target capture. Heat induced epitope retrieval was observed for approximately half of the targeted proteins, and resulted in the discovery of different candidate markers for prostate cancer. Several antibodies towards the prostate cancer candidate biomarker CNDP1 were generated, epitope mapped and evaluated in a bead based sandwich immunoassay, as presented in Papers IV and V. Furthermore, the developed sandwich immunoassay targeting multiple distinct CNDP1 epitopes in more than 1000 samples, confirmed the association of CNDP1 levels to aggres- sive prostate cancer and more specifically to prostate cancer patients with regional lymph node metastasis (Paper V). As an outcome of the present investigations and in parallel to studies within the Biobank profiling research group, valuable lessons from study design and multiplex antibody analysis of plasma within biomarker discovery to experimental, technical and biological verifications have been collected.QC 20130821
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Jin, Yan Nan. "Plasma phytochemicals : mediators of CVD risk reduction and biomarkers of fruit and vegetable intake." Thesis, University of Reading, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578030.
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This research is concerned with the analysis of data from two dietary intervention studies. The first study investigated the effects of acute ingestion of low-dose blackcurrant juice drink on the antioxidant capacity of plasma, acute measures of vascular reactivity and biomarkers of endothelial function: The second study was a randomized, controlled, dietary intervention study (FLAVURS) (n = 154) in which the test groups had sequential increases of 2,4 and 6 portions of high flavonoid or low flavonoid fruits and vegetables (F & V) every 6 weeks across an 18 week period. This thesis reports the dietary strategy to increase the amount and types of fruits and vegetables consumed by a free living population. Selected data from the study was used to develop an improved biomarker for F & V consumption, and data from the study was also used to investigate the association between plasma antioxidants and markers of vascular reactivity and endothelial function. The acute study showed that consumption of a 20% blackcurrant juice drink caused increases in plasma vitamin C (P=0.006), and urinary anthocyanins (P